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Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production ( erythropoiesis) in the bone marrow. Low levels of EPO (around 10  mU/mL) are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO (up to 10 000 mU/mL) include any anemia, and hypoxemia due to chronic lung disease. Erythropoietin is produced by interstitial fibroblasts in the kidney in close association with the peritubular capillary and proximal convoluted tubule. It is also produced in perisinusoidal cells in the liver. Liver production predominates in the fetal and perinatal period; renal production predominates in adulthood. It is homologous with thrombopoietin.
Exogenous In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system. Economics In an economic model, an exogen ...
erythropoietin, recombinant human erythropoietin (rhEPO), is produced by
recombinant DNA technology Molecular cloning is a set of experimental methods in molecular biology that are used to assemble recombinant DNA molecules and to direct their replication within host organisms. The use of the word ''cloning'' refers to the fact that the meth ...
in cell culture and are collectively called
erythropoiesis-stimulating agent Erythropoiesis-stimulating agents (ESA) are medications which stimulate the bone marrow to make red blood cells. They are used to treat anemia due to end stage kidney disease, chemotherapy, major surgery, or certain treatments in HIV/AIDS. In ...
s (ESA): two examples are
epoetin alfa Epoetin alfa is a human erythropoietin produced in cell culture using recombinant DNA technology. Authorised by the European Medicines Agency on 28 August 2007, it stimulates erythropoiesis (increasing red blood cell levels) and is used to t ...
and
epoetin beta Epoetin beta ( rINN) is a synthetic, recombinant form of erythropoietin, a protein that promotes the production of red blood cells. It is an erythropoiesis-stimulating agent (ESA) that is used to treat anemia, commonly associated with chronic k ...
. ESAs are used in the treatment of anemia in chronic kidney disease, anemia in
myelodysplasia A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms ma ...
, and in anemia from cancer chemotherapy. Risks of therapy include death, myocardial infarction, stroke,
venous thromboembolism Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
, and tumor recurrence. Risk increases when EPO treatment raises hemoglobin levels over 11 g/dL to 12 g/dL: this is to be avoided. rhEPO has been used illicitly as a performance-enhancing drug. It can often be detected in blood, due to slight differences from the endogenous protein; for example, in features of posttranslational modification.


Pharmacology

EPO is highly
glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
(40% of total molecular weight), with half-life in blood around 5 h. EPO's half-life may vary between endogenous and various recombinant versions. Additional glycosylation or other alterations of EPO via recombinant technology have led to the increase of EPO's stability in blood (thus requiring less frequent injections).


Function


Red blood cell production

Erythropoietin is an essential hormone for red blood cell production. Without it, definitive erythropoiesis does not take place. Under hypoxic conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting CFU-E, pro erythroblast and basophilic erythroblast subsets in the differentiation. Erythropoietin has its primary effect on red blood cell progenitors and precursors (which are found in the bone marrow in humans) by promoting their survival through protecting these cells from apoptosis, or cell death. Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g., IL-3, IL-6, glucocorticoids, and SCF) involved in the development of erythroid lineage from multipotent progenitors. The burst-forming unit-erythroid ( BFU-E) cells start erythropoietin receptor expression and are sensitive to erythropoietin. Subsequent stage, the colony-forming unit-erythroid ( CFU-E), expresses maximal erythropoietin receptor density and is completely dependent on erythropoietin for further differentiation. Precursors of red cells, the proerythroblasts and basophilic erythroblasts also express erythropoietin receptor and are therefore affected by it.


Nonhematopoietic roles

Erythropoietin was reported to have a range of actions beyond stimulation of erythropoiesis including vasoconstriction-dependent hypertension, stimulating angiogenesis, and promoting cell survival via activation of EPO receptors resulting in anti-apoptotic effects on ischemic tissues. However this proposal is controversial with numerous studies showing no effect. It is also inconsistent with the low levels of EPO receptors on those cells. Clinical trials in humans with ischemic heart, neural and renal tissues have not demonstrated the same benefits seen in animals. In addition some research studies have shown its neuroprotective effect on diabetic neuropathy, however these data were not confirmed in clinical trials that have been conducted on the deep peroneal, superficial peroneal, tibial and sural nerves.


Mechanism of action

Erythropoietin has been shown to exert its effects by binding to the erythropoietin receptor (EpoR). EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a JAK2 signalling cascade. This initiates the STAT5, PIK3 and Ras MAPK pathways. This results in differentiation, survival and proliferation of the erythroid cell. SOCS1, SOCS3 and CIS are also expressed which act as negative regulators of the cytokine signal. High level erythropoietin receptor expression is localized to erythroid progenitor cells. While there are reports that EPO receptors are found in a number of other tissues, such as heart, muscle, kidney and peripheral/central nervous tissue, those results are confounded by nonspecificity of reagents such as anti-EpoR antibodies. In controlled experiments, a functional EPO receptor is not detected in those tissues. In the bloodstream, red cells themselves do not express erythropoietin receptor, so cannot respond to EPO. However, indirect dependence of red cell longevity in the blood on plasma erythropoietin levels has been reported, a process termed neocytolysis. In addition, there is conclusive evidence that EPO receptor expression is upregulated in brain injury.


Synthesis and regulation

Erythropoietin levels in blood are quite low in the absence of anemia, at around 10 mU/mL. However, in hypoxic stress, EPO production may increase up to 1000-fold, reaching 10 000 mU/mL of blood. In adults, EPO is synthesized mainly by interstitial cells in the peritubular capillary bed of the renal cortex, with additional amounts being produced in the liver, and the
pericytes Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood c ...
in the brain. Regulation is believed to rely on a feedback mechanism measuring blood oxygenation and iron availability. Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors, are hydroxylated and proteosomally digested in the presence of oxygen and iron. During normoxia GATA2 inhibits the promoter region for EPO. GATA2 levels decrease during hypoxia and allow the promotion of EPO production. Erythropoietin production can be induced by HIF-2α as well as by PGC-1α. Erythropoietin also activates these factors, resulting in Erythropoietins available for use as
therapeutic agents A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
are produced by
recombinant DNA technology Molecular cloning is a set of experimental methods in molecular biology that are used to assemble recombinant DNA molecules and to direct their replication within host organisms. The use of the word ''cloning'' refers to the fact that the meth ...
in cell culture, and include Epogen/Procrit (
epoetin alfa Epoetin alfa is a human erythropoietin produced in cell culture using recombinant DNA technology. Authorised by the European Medicines Agency on 28 August 2007, it stimulates erythropoiesis (increasing red blood cell levels) and is used to t ...
) and Aranesp (
darbepoetin alfa Darbepoetin alfa (International Nonproprietary Name, INN) is a re-engineered form of erythropoietin containing 5 amino acid changes (N30, T32, V87, N88, T90) resulting in the creation of 2 new sites for N-linked carbohydrate addition. It has a 3- ...
); they are used in treating anemia resulting from chronic kidney disease, chemotherapy induced anemia in patients with cancer, inflammatory bowel disease ( Crohn's disease and ulcerative colitis) and
myelodysplasia A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms ma ...
from the treatment of cancer ( chemotherapy and radiation). The package inserts include boxed warnings of increased risk of death, myocardial infarction, stroke,
venous thromboembolism Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
, and tumor recurrence, particularly when used to increase the hemoglobin levels to more than 11 g/dL to 12 g/dL.


History

In 1905, Paul Carnot proposed the idea that a hormone regulates the production of red blood cells. After conducting experiments on rabbits subject to
bloodletting Bloodletting (or blood-letting) is the withdrawal of blood from a patient to prevent or cure illness and disease. Bloodletting, whether by a physician or by leeches, was based on an ancient system of medicine in which blood and other bodily f ...
, Carnot and his graduate student
Clotilde-Camille Deflandre Clotilde-Camille Deflandre (November 21, 1871 – June 7, 1946) was a French scientist primarily known for her discovery with her mentor Paul Carnot of ''Hémopoïétine''" (erythropoietin). She also pioneered work that led to the development of ...
attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff and Eeva Jalavisto called the hemopoietic substance 'erythropoietin'. K.R. Reissman and Allan J. Erslev demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increase hematocrit. This substance was purified and confirmed as erythropoietin. In 1977, Goldwasser and Kung purified EPO. Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated. Synthetic EPO was first successfully used to correct anemia in 1987. In 1985, Lin ''et al'' isolated the human erythropoietin gene from a genomic phage library and used it to produce EPO. In 1989, the US Food and Drug Administration (FDA) approved the hormone
Epogen Epoetin alfa is a human erythropoietin produced in cell culture using recombinant DNA technology. Authorised by the European Medicines Agency on 28 August 2007, it stimulates erythropoiesis (increasing red blood cell levels) and is used to treat ...
for use in certain anemias.
Gregg L. Semenza Gregg Leonard Semenza (born July 12, 1956) is a Pediatrician and Professor of Genetic Medicine at the Johns Hopkins School of Medicine. He serves as the director of the vascular program at the Institute for Cell Engineering. He is a 2016 recipi ...
and
Peter J. Ratcliffe Sir Peter John Ratcliffe, FRS, FMedSci (born 14 May 1954) is a British Nobel Laureate physician-scientist who is trained as a nephrologist. He was a practising clinician at the John Radcliffe Hospital, Oxford and Nuffield Professor of Clinical ...
studied the EPO gene and its oxygen-dependent regulation. Along with
William Kaelin Jr. William G. Kaelin Jr. (born November 23, 1957) is an American Nobel Laureate physician-scientist. He is a professor of medicine at Harvard University and the Dana–Farber Cancer Institute. His laboratory studies tumor suppressor proteins. In 201 ...
, they were awarded the 2019 Nobel Prize in Physiology or Medicine for their discovery of hypoxia-inducible factor (HIF), which regulates the EPO gene, as well as other genes, in response to hypoxia.


Biosimilars

In December 2007, Retacrit and Silapo (both epoetin zeta) were approved for use in the European Union.


Usage as doping product

As a performance-enhancing drug, EPO has been banned since the early 1990s, but a first test was not available until the
2000 Summer Olympics The 2000 Summer Olympics, officially the Games of the XXVII Olympiad and also known as Sydney 2000 ( Dharug: ''Gadigal 2000''), the Millennium Olympic Games or the Games of the New Millennium, was an international multi-sport event held from ...
. Before this test was available, some athletes were sanctioned after confessing to having used EPO, for example in the Festina affair, when a car with doping products for the Festina cycling team was found. The first doping test in cycling was used in the
2001 La Flèche Wallonne The 2001 La Flèche Wallonne was the 65th edition of La Flèche Wallonne cycle race and was held on 18 April 2001. The race started in Charleroi and finished in Huy. The race was won by Rik Verbrugghe of the Lotto team. General classification ...
. The first rider to test positive in that race was
Bo Hamburger Bo Hamburger (born 24 May 1970 in Frederiksberg) is a Danish former professional road racing cyclist. He retired in 2006. Biography After ending his career, Hamburger started a building company and a bike shop. He was the leading directeur spor ...
, although he was later acquitted because his B-sample was not conclusive. The U.S. Postal Service Pro Cycling Team, under the leadership of Lance Armstrong and
Johan Bruyneel Johan Bruyneel (born 23 August 1964) is a Belgian former professional road bicycle racer and a former directeur sportif for UCI ProTour team , and (later known as Discovery Channel), a US-based UCI ProTour cycling team. On 25 October 2018, the ...
, ran a sophisticated doping program that lasted for many years during the late 1990s and early 2000s. Erythropoietin was a common substance used by the cyclists. A 2007 study showed that EPO has a significant effect on exercise performance, but a 2017 study showed that the effects of EPO administered to amateur cyclists was not distinguishable from a placebo. In March 2019, American mixed martial artist and former UFC Bantamweight Champion T.J. Dillashaw tested positive for EPO in a drug test administered by USADA, and was stripped of the UFC bantamweight title and suspended for 2 years. EPO has been used as a performance enhancing agent in horse racing since at least 2019.


References


Further reading

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External links

* * {{Authority control Cytokines Growth factors Hormones of the kidneys Nephrology procedures World Anti-Doping Agency prohibited substances